In general, the polymers used as supports for controlled-release medicaments must be biocompatible, non-toxic and free of impurities. In particular, biodegradable polymers must give non-toxic, non-carcinogenic and non-teratogenic degradation products and must be readily eliminated.
The factors which influence the biodegradability are the particle sizes, morphology and chemical structure. Among these factors, the crystallinity has an important role, both from the point of view of the biodegradability and from the technological point of view of working of the polymers.
The common techniques of microencapsulation comprise coacervation, evaporation of the emulsified solvent and coextrusion. The latter is the preferred technique since it avoids the use of solvents and consequently poses no toxicological problems arising from residues thereof.
Extrudable polymers must be stable at the temperature of coextrusion, and must have a softening temperature which is not too high, to avoid decomposition of the medicament, but not too low either, to avoid problems of conservation.
Examples of pharmaceutical formulations in which the medicament (active principle) is incorporated in a biodegradable matrix are known in the literature. See for example "Biodegradable Polymers as Drug Delivery Systems", ed. by M. Chasin and R. Langer, Marcel Dekker Inc., New York 1990; "Methods in Enzymology, Vol. 112, Drug and Enzyme Targeting, Part A, ed. by K. J. Widder and R. Green, Academic Press. Inc., Orlando, Fla., 1985; "Formes Pharmaceutiques Nouvelles", P. Buri, F. Puisieux, E. Dalker, J. P. Benoit, Technique and Documentation (Lavoisier), Paris, 1985; "Biodegradable Polymers for controlled release of peptides and proteins", F. G. Hutchison and B. J. A. Furr, in Drug Carrier
Systems, F. H. D. Roerdink and A. M. Kroom eds., John Wiley and Sons, Chichester, 1989; "Controlled Release of Biologically Active Agents" Richard Baker, John Wiley and Sons, New York, 1987.
Many types of polymers have been used for the above-mentioned purposes, and, among these, polycarbonates have demonstrated suitable biocompatiblity characteristics.
Kawaguchi et al. (Chem. Pharm. Bull. Vol. 31, n. 4, 1400-1403, 1983) describe the biodegradability of tablets made of polyethylene carbonate and polypropylene carbonate and the possibility of obtaining biocompatible materials of programmed degradation using suitable mixtures of the two polycarbonates.
Polycarbonates are polymers which have been known for a long time. Aliphatic polycarbonates are known, for example, from DE 2,546,534, published on Apr. 28, 1977, JP 6224190, published on Oct. 22, 1987 and JP 1009225, published on Jan. 12, 1989, these patents proposing them as plasticizers and intermediates for the preparation of polyurethanes (see also U.S. Pat. No. 4,105,641, granted on Aug. 8, 1978).
Polycarbonates of homo- and copolymeric nature have also been proposed. U.S. Pat. No. 4,716,203 (American Cyanamid), granted on Dec. 29, 1987, describes diblock and triblock copolymers having a first block of glycolic acid ester linked with trimethylene carbonate; triblock copolymers have an intermediate block obtained from ethylene oxide homopolymer or ethylene oxide/cyclic ether copolymer, or alternatively from macrocyclic ether copolymers. These copolymers are bioabsorbable and are indicated for the finishing of synthetic surgical threads.
International patent application WO 89/05664, in the name of Allied-Signal Inc., published on Jun. 29, 1989, describes medical devices formed partly or totally of polycarbonate homopolymers or copolymers which can contain polyether-polyamine portions in the polymer chain.
European patent application EP 0,427,185, in the name of Boehringer Ingelheim, published on Jan. 15, 1991, describes copolymers obtained from trimethylene carbonate and optically inactive lactides, which are useful for the manufacture of surgical grafts.
International patent applications WO 92/22600 and WO 95/12629, in the name of the Applicant, describe polyester polycarbonate random block copolymers which are useful as biodegradable matrices.
One problem which is posed in the use of biodegradable matrices is the biodegradation time of the material, which is usually too short.
The rate of degradation is a function of the hydrolytic susceptibility of the polyester blocks.
Another problem consists of the presence of crystallinity in the material. Indeed, biodegradable materials having a certain degree of crystallinity have markedly longer degradation times when compared with a completely amorphous analogous material. Therefore, the presence of a crystalline phase allows the development of products which are useful when long degradation times are required. Another appreciable effect of this factor is a substantial increase in the mechanical properties, for example the elastic modulus. This is potentially useful when a use as subcutaneous implants is envisaged. However, this crystallinity is lost when the material comes into contact with an aqueous medium or when it absorbs moisture.
Moreover, in the working of polymers by extrusion (one of the preferred methods), the melting range must be such as to be able to work the polymer easily without adversely affecting the active principle contained therein.
The preparation of block polyesters based on poly(caprolactone) and PLGA is described in the literature (C.A. 114: 229486y; C.A. 109: 190883e; C.A. 104: 89084s; C.A. 116: 21504w). These materials are prepared by one- or two-step copolymerization processes by means of ring opening of cyclic monomers.
These processes lead to systems which can only contain more than two or three blocks with difficulty. Moreover, the nature of the reaction and the method used do not allow full control of the structure of the product obtained. There are two fundamental reasons for this, which are well discussed in the publications cited. The first limiting factor consists of the diverse reactivity presented by various cyclic monomers (caprolactone, lactide and glycolide). This greatly limits the control of the length of the various blocks, and allows the production of diblock, or at the most triblock, systems. Another factor, which is by far more limiting, consists of the occurrence, during the polymerization reactions, of structure randomization phenomena; that is to say that as the conversion increases, the block structure converts into a random structure of statistical type.